tbuckley/cabot-search huggingface dataset:
Flashback Foreword: Afatinib for the Treatment of Epidermal Growth Factor Receptor Mutation–Positive Non–Small-Cell Lung Cancer
Authors: Thomas E. Stinchcombe
Journal: Journal of Clinical Oncology (2023)

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. May 26, 2023 ARTICLE CITATION DOI: 10.1200/JCO.22.02848 Journal of Clinical Oncology - published online before print May 26, 2023 PMID: 37235975 Flashback Foreword: Afatinib for the Treatment of Epidermal Growth Factor Receptor Mutation–Positive Non–Small-Cell Lung Cancer Thomas E. Stinchcombe , MD1,2xThomas E. StinchcombeSearch for articles by this author Show More 1Associate Editor, Journal of Clinical Oncology, Alexandria, VA2Duke Cancer Institute, Durham, NC https://doi.org/10.1200/JCO.22.02848 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn 2013, Sequist et al1 published in JCO the results of a randomized trial demonstrating that afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, resulted in a superior objective response rate and longer progression-free survival in patients with EGFR-mutant non–small-cell lung cancer compared with cisplatin and pemetrexed. This trial, which included patients with uncommon mutations of EGFR, resulted in afatinib being considered one of several standard-of-care EGFR tyrosine kinase inhibitors.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTFlashback Foreword: Afatinib for the Treatment of Epidermal Growth Factor Receptor Mutation–Positive Non–Small-Cell Lung CancerThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Thomas E. StinchcombeThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: EMD Serono, Janssen Oncology, Turning Point Therapeutics, Sanofi/Aventis, GlaxoSmithKline, Genentech/Roche, Daiichi Sankyo/Astra Zeneca, Takeda, Eisai/H3 Biomedicine, G1 Therapeutics, Spectrum PharmaceuticalsResearch Funding: AstraZeneca (Inst), Takeda (Inst), Regeneron (Inst), Seattle Genetics (Inst), Mirati Therapeutics (Inst), Genentech/Roche (Inst)No other potential conflicts of interest were reported. Companion Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations
Concomitant exposure to air pollution, green space, and noise and risk of stroke: a cohort study from Denmark
Authors: Aslak H. Poulsen, Mette Sørensen, Ulla A. Hvidtfeldt, Jesper H. Christensen, Jørgen Brandt, Lise M. Frohn, Matthias Ketzel, Christopher Andersen, Steen Solvang Jensen, Thomas Münzel, Ole Raaschou-Nielsen
Journal: The Lancet Regional Health - Europe (2023)

Air pollution, road traffic noise, and green space are correlated factors, associated with risk of stroke. We investigated their independent relationship with stroke in multi-exposure analyses and estimated their cumulative stroke burden.For all persons, ≥50 years of age and living in Denmark from 2005 to 2017, we established complete address histories and estimated running 5-year mean exposure to fine particles (PM2.5), ultrafine particles, elemental carbon, nitrogen dioxide (NO2), and road traffic noise at the most, and least exposed façade. For air pollutants, we estimated total, and non-traffic contributions. Green space around the residence was estimated from land use maps. Hazard ratios (HR) and 95% confidence limits (CL) were estimated with Cox proportional hazards models and used to calculate cumulative risk indices (CRI). We adjusted for the individual and sociodemographic covariates available in our dataset (which did not include information about individual life styles and medical conditions).The cohort accumulated 18,344,976 years of follow-up and 94,256 cases of stroke. All exposures were associated with risk of stroke in single pollutant models. In multi-pollutant analyses, only PM2.5 (HR: 1.058, 95% CI: 1.040-1.075) and noise at most exposed façade (HR: 1.033, 95% CI: 1.024-1.042) were independently associated with a higher risk of stroke. Both noise and air pollution contributed substantially to the CRI (1.103, 95% CI: 1.092-1.114) in the model with noise, green space, and total PM2.5 concentrations.Environmental exposure to air pollution and noise were both independently associated with risk of stroke.Health Effects Institute (HEI) (Assistance Award No. R-82811201).
Microcarriers promote the through interface movement of mouse trophoblast stem cells by regulating stiffness
Authors: Zili Gao, Jia Guo, Bo Gou, Zhen Gu, Tan Jia, Sinan Ma, Liyuan Jiang, Wenli Liu, Lixun Zhou, Qi Gu
Journal: Bioactive Materials (2023)

Mechanical force is crucial in the whole process of embryonic development. However, the role of trophoblast mechanics during embryo implantation has rarely been studied. In this study, we constructed a model to explore the effect of stiffness changes in mouse trophoblast stem cells (mTSCs) on implantation: microcarrier was prepared by sodium alginate using a droplet microfluidics system, and mTSCs were attached to the microcarrier surface with laminin modifications, called T(micro). Compared with the spheroid, formed by the self-assembly of mTSCs (T(sph)), we could regulate the stiffness of the microcarrier, making the Young's modulus of mTSCs (367.70 ± 79.81 Pa) similar to that of the blastocyst trophoblast ectoderm (432.49 ± 151.90 Pa). Moreover, T(micro) contributes to improve the adhesion rate, expansion area and invasion depth of mTSCs. Further, T(micro) was highly expressed in tissue migration-related genes due to the activation of the Rho-associated coiled-coil containing protein kinase (ROCK) pathway at relatively similar modulus of trophoblast. Overall, our study explores the embryo implantation process with a new perspective, and provides theoretical support for understanding the effect of mechanics on embryo implantation.
Protection of Catalytic Cofactors by Polypeptides as a Driver for the Emergence of Primordial Enzymes
Authors: Luis I Gutierrez-Rus, Gloria Gamiz-Arco, J A Gavira, Eric A Gaucher, Valeria A Risso, Jose M Sanchez-Ruiz
Journal: Molecular Biology and Evolution (2023)

Abstract Enzymes catalyze the chemical reactions of life. For nearly half of known enzymes, catalysis requires the binding of small molecules known as cofactors. Polypeptide-cofactor complexes likely formed at a primordial stage and became starting points for the evolution of many efficient enzymes. Yet, evolution has no foresight so the driver for the primordial complex formation is unknown. Here, we use a resurrected ancestral TIM-barrel protein to identify one potential driver. Heme binding at a flexible region of the ancestral structure yields a peroxidation catalyst with enhanced efficiency when compared to free heme. This enhancement, however, does not arise from protein-mediated promotion of catalysis. Rather, it reflects the protection of bound heme from common degradation processes and a resulting longer lifetime and higher effective concentration for the catalyst. Protection of catalytic cofactors by polypeptides emerges as a general mechanism to enhance catalysis and may have plausibly benefited primordial polypeptide-cofactor associations.
Double-scope endoscopic submucosal dissection of superficial laryngeal cancer to preserve the superior laryngeal nerve
Authors: Yoshinori Horikawa, Koichi Hamada, Yoshiki Shiwa, Yusuke Mada, Kae Techigawara, Masafumi Ishikawa, Akiyoshi Ishiyama
Journal: Endoscopy (2023)

Endoscopic submucosal dissection (ESD) is a minimally invasive surgery for laryngeal cancers [1], during which nerve sparing is necessary to preserve function [2]. The internal branch of the superior laryngeal nerve (ibSLN) enters the parietal recess mucosa and is distributed in the submucosa of the larynx and hypopharynx [3]. The ibSLN controls sensory perception. Damage to this may result in loss of the laryngeal cough reflex, resulting in aspiration pneumonia. A previous study reported the efficacy of double-scope ESD (ds-ESD) for laryngeal cancers [4]. We believe that ds-ESD is effective in nerve preservation. Here, we report a case of successful nerve-sparing ESD using the double-scope method.
Unraveling Heterogeneity in the Aging Hematopoietic Stem Cell Compartment: An Insight From Single-cell Approaches
Authors: Fei Yang, Craig Nourse, G. Vignir Helgason, Kristina Kirschner
Journal: HemaSphere (2023)

Specific cell types and, therefore, organs respond differently during aging. This is also true for the hematopoietic system, where it has been demonstrated that hematopoietic stem cells alter a variety of features, such as their metabolism, and accumulate DNA damage, which can lead to clonal outgrowth over time. In addition, profound changes in the bone marrow microenvironment upon aging lead to senescence in certain cell types such as mesenchymal stem cells and result in increased inflammation. This heterogeneity makes it difficult to pinpoint the molecular drivers of organismal aging gained from bulk approaches, such as RNA sequencing. A better understanding of the heterogeneity underlying the aging process in the hematopoietic compartment is, therefore, needed. With the advances of single-cell technologies in recent years, it is now possible to address fundamental questions of aging. In this review, we discuss how single-cell approaches can and indeed are already being used to understand changes observed during aging in the hematopoietic compartment. We will touch on established and novel methods for flow cytometric detection, single-cell culture approaches, and single-cell omics.
Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis
Authors: Yuyi Xu, Ming Zhao, Jinxue Cao, Ting Fang, Jian Zhang, Yanli Zhen, Fangling Wu, Xiaohui Yu, Yaming Liu, Ji Li, Dongkai Wang
Journal: Acta Pharmaceutica Sinica B (2023)

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.
Unique double guidewire technique using a guidewire perforating the diverticulum for a difficult biliary cannulation
Authors: Kazuya Koizumi, Kento Shionoya, Sakue Masuda, Jun Kubota, Karen Kimura
Journal: Endoscopy (2023)

Biliary cannulation of an intradiverticular papilla, classified type 1 as per the Li-Tanaka classification, is sometimes challenging [1]. Although in cases with difficult biliary cannulation the pancreatic duct guidewire placement technique is useful [2] [3], placing the guidewire in the pancreatic duct is sometimes difficult. We report a successful case of biliary cannulation in a patient with an intradiverticular papilla using an unusual double guidewire technique taking advantage of a guidewire perforating the diverticulum.
DLBCL-associated NOTCH2 mutations escape ubiquitin-dependent degradation and promote chemoresistance
Authors: Nan Zhou, Jaewoo Choi, Grant Grothusen, Bang-Jin Kim, Diqiu Ren, Zhendong Cao, Yiman Liu, Qinglan Li, Arati Inamdar, Thomas Beer, Hsin-Yao Tang, Eric Perkey, Ivan Maillard, Roberto Bonasio, Junwei Shi, Marco Ruella, Liling Wan, Luca Busino
Journal: Blood (2023)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Up to 40% of patients with DLBCL display refractory disease or relapse after standard chemotherapy treatment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]), leading to significant morbidity and mortality. The molecular mechanisms of chemoresistance in DLBCL remain incompletely understood. Using a cullin–really interesting new gene (RING) ligase-based CRISPR-Cas9 library, we identify that inactivation of the E3 ubiquitin ligase KLHL6 promotes DLBCL chemoresistance. Furthermore, proteomic approaches helped identify KLHL6 as a novel master regulator of plasma membrane–associated NOTCH2 via proteasome-dependent degradation. In CHOP-resistant DLBCL tumors, mutations of NOTCH2 result in a protein that escapes the mechanism of ubiquitin-dependent proteolysis, leading to protein stabilization and activation of the oncogenic RAS signaling pathway. Targeting CHOP-resistant DLBCL tumors with the phase 3 clinical trial molecules nirogacestat, a selective γ-secretase inhibitor, and ipatasertib, a pan-AKT inhibitor, synergistically promotes DLBCL destruction. These findings establish the rationale for therapeutic strategies aimed at targeting the oncogenic pathway activated in KLHL6- or NOTCH2-mutated DLBCL.
A simulator based on the morphology of an actual stomach for training in endoscopic therapy: is this where beginners should be starting?
Authors: Jiyu Zhang, Miao Shi, Saif Ullah, Lixia Zhao, Bing-Rong Liu
Journal: Endoscopy (2023)

At present, the design of most endoscopic training simulators is not based on actual gastric morphology [1] [2] [3]. We therefore developed a simulator for endoscopic therapy training that was based on the morphology of an actual stomach. Starting from computed tomographic images of a stomach, a standard gastric morphological structure was made using computer modeling and 3 D printing technology ([Fig. 1 a–c]). To simulate the position of the human stomach during gastroscopy, a container was designed to support and hold the simulator in a fixed position ([Fig. 1 d]). Compared to traditional simulators, which are not designed on the basis of real gastric morphology, our simulator preserves the original structure of the stomach as much as possible, especially in regard to the fundus and the angular incisure ([Fig. 2 a]). This allows trainees to experience clinical gastroscopy in a way that is as realistic as possible.
Rescue using NOTES during endoscopic ultrasound-guided hepaticogastrostomy, after maldeployment of fully covered self-expandable metal stent
Authors: Xiaohua Ye, Xiaoju Su, Ting Yang, Bo Li, Lei Wang
Journal: Endoscopy (2023)

A 56-year-old man was admitted to our hospital with obstructive jaundice caused by extrahepatic cholangiocarcinoma that developed from a congenital choledochal cyst ([Fig. 1]). Endoscopic retrograde cholangiopancreatography was hampered by ampullary effacement caused by malignant invasion. Endoscopic ultrasound (EUS)-guided hepaticogastrostomy was therefore attempted using an 8-cm fully covered self-expandable metal stent (FCSEMS) (Boston Scientific, Marlborough, Massachusetts, USA).
Bleeding giant pseudoaneurysm non-visualized on arterial phase imaging: Endoscopic ultrasound-guided angioembolization to the rescue
Authors: Jayanta Samanta, Jahnvi Dhar, Mithu Bhowmick, Ashutosh Ishan, Antriksh Kumar, Pankaj Gupta, Saroj Kant Sinha
Journal: Endoscopy (2023)

A 51-year-old man, with known diabetes and coronary artery disease and a history of acute pancreatitis, presented with melena for 1 day. Investigations revealed anemia (hemoglobin 6.8 gm/dl) with tachycardia. After initial resuscitation, computed tomography (CT) angiography was done. In the arterial phase, no extravasation or aneurysm was noted ([Fig. 1]). However, in the venous phase, contrast filling was noted with a giant pseudoaneurysm measuring 7.2 × 6.2 × 9.7 cm, likely arising from the splenic vessel ([Fig. 2]). The patient, being a poor candidate for radiological endovascular therapy (non-visualization on arterial phase, narrow neck) as well as surgery (multiple comorbidities), was planned for endoscopic ultrasound (EUS)-guided angioembolization. EUS-guided localization of the aneurysm was done and Doppler showed turbulent blood flow in the giant pseudoaneurysm ([Fig. 3]). It was punctured with a 19-G needle (EZ Shot3 Plus; Olympus Medical, Tokyo, Japan) and blood aspirated to confirm the position. After flushing the needle with saline, four Nester coils (20 mm × 14 cm) were deployed one after the other. Using this coil-complex as a scaffold, 4 ml of cyanoacrylate glue was injected. The coil-glue cast formed caused thrombosis of the blood contents, which gradually increased in size and slowed the intravascular turbulence ([Fig. 4] ). On further observation for another 1 minute, the whole aneurysm showed formation of an echogenic thrombus with minimal flow ([Video 1]). A repeat EUS 48 hours later showed complete obliteration of the pseudoaneurysm with no flow ([Fig. 5]), and CT revealed coil artifacts with no filling in the venous phase. At the 1-year follow-up, the patient was doing fine with no further bleeding episodes.
Patients With Microscopic Colitis Are at Higher Risk of Major Adverse Cardiovascular Events: A Matched Cohort Study
Authors: Anders Forss, David Bergman, Bjorn Roelstraete, Johan Sundström, Ali Mahdi, Hamed Khalili, Jonas F. Ludvigsson
Journal: Clinical Gastroenterology and Hepatology (2023)

Inflammatory diseases are associated with an increased risk of incident major adverse cardiovascular events (MACE). However, data on MACE are lacking in large population-based histopathology cohorts of microscopic colitis (MC).
The largely neglected ecological role of oceanic pelagic fungi
Authors: Eva Breyer, Federico Baltar
Journal: Trends in Ecology & Evolution (2023)

Most investigations into ocean ecology and biogeochemistry have tended to focus on marine bacteria, archaea, and protists, while pelagic fungi (mycoplankton) have traditionally been neglected and considered to reside only in association with benthic solid substrates. Nevertheless, recent studies have revealed that pelagic fungi are distributed ubiquitously throughout the water column in every ocean basin and play an active role in the degradation of organic matter and the cycling of nutrients. We review the current status of knowledge on the ecology of mycoplankton and highlight knowledge gaps and challenges. These findings underscore the need to recognize this neglected kingdom as significant contributors to the organic matter cycling and ecology of the oceans.
An Overview of Targeted Therapies in Acute Myeloid Leukemia
Authors: Sven Turkalj, Felix A. Radtke, Paresh Vyas
Journal: HemaSphere (2023)

Acute myeloid leukemia (AML) is the most aggressive adult leukemia, characterized by clonal differentiation arrest of progenitor or precursor hematopoietic cells. Intense preclinical and clinical research has led to regulatory approval of several targeted therapeutics, administered either as single agents or as combination therapies. However, the majority of patients still face a poor prognosis and disease relapse frequently occurs due to selection of therapy-resistant clones. Hence, more effective novel therapies, most likely as innovative, rational combination therapies, are urgently needed. Chromosomal aberrations, gene mutations, and epigenetic alterations drive AML pathogenesis but concurrently provide vulnerabilities to specifically target leukemic cells. Other molecules, either aberrantly active and/or overexpressed in leukemic stem cells, may also be leveraged for therapeutic benefit. This concise review of targeted therapies for AML treatment, which are either approved or are being actively investigated in clinical trials or recent preclinical studies, provides a flavor of the direction of travel, but also highlights the current challenges in AML treatment.
First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma
Authors: Julius Strauss, Jean-Laurent Deville, Mario Sznol, Alain Ravaud, Marco Maruzzo, Russell K Pachynski, Theodore S Gourdin, Michele Maio, Luc Dirix, Jeffrey Schlom, Renee N Donahue, Yo-Ting Tsai, XiaoZhe Wang, Yulia Vugmeyster, Frank Beier, Joerg Seebeck, Andreas Schroeder, Sarah Chennoufi, James L Gulley
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background In preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab. Methods In the dose-escalation part of JAVELIN IL-12 ( NCT02994953 ), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1–4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated. Results At data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug–drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges. Conclusions M9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.